SB-497115 (Oral Thrombopoietin Receptor Agonist) Versus Placebo In Adult Cancer Patients Receiving Chemotherapy

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT00102726

Collaborator

(none)

183

Enrollment

Locations

Arms

Duration (Months)

1.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

SB497115 is an oral agent which activates the thrombopoietin receptor and increases platelet counts in healthy volunteers. This study is examining several different doses of SB497115 versus placebo as treatment for patients with advanced solid tumors scheduled to receive chemotherapy with carboplatin and paclitaxel every 21 days. Patients will receive SB497115 on days 2-11 of each 21 day cycle for at least 2 cycles of chemotherapy and for a maximum of 8 cycles of chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Thrombocytopaenia	Drug: SB497115 Other: Placebo	Phase 2

Detailed Description

A Double-Blind, Randomized, Multicenter, Placebo-Controlled, Parallel Group, Dose Ranging Study to Assess the Efficacy, Safety, and Pharmacokinetics of an Oral Thrombopoietin Receptor Agonist (SB-497115-GR) Administered at 50, 75, and 100 mg to Cancer Patients Receiving Multiple Cycles of Chemotherapy

Study Design

Study Type:

Interventional

Actual Enrollment :

183 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Double-Blind, Randomized, Multicenter, Placebo-Controlled, Parallel Group, Dose Ranging Study to Assess the Efficacy, Safety, and Pharmacokinetics of an Oral Thrombopoietin Receptor Agonist(SB497115-GR) Administered at 50, 75, and 100 mg to Cancer Patients Receiving Multiple Cycles of Chemotherapy

Study Start Date :

Feb 1, 2005

Actual Primary Completion Date :

Feb 1, 2007

Actual Study Completion Date :

Feb 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1 SB-497115-GR 50mg. administered orally daily on days 2 through 11 for each 21-day cycle.	Drug: SB497115 SB497115/Placebo will be administered for at least 2 cycles. Additional cycles are permited if: 1) chemotherapy is continued, 2) the subject appears to be benefitting from the study drug, and 3) the subject has not encountered greater than moderate toxicity with the study drug. The maximum number of cycles would be 8.
Active Comparator: Arm 2 SB-497115-GR 75 mg administered orally dailey on days 2-11 of each 21-day cycle.	Drug: SB497115 SB497115/Placebo will be administered for at least 2 cycles. Additional cycles are permited if: 1) chemotherapy is continued, 2) the subject appears to be benefitting from the study drug, and 3) the subject has not encountered greater than moderate toxicity with the study drug. The maximum number of cycles would be 8.
Active Comparator: Arm 3 SB-497115 100mg administered orally daily on days 2 through 11 of each 21-day cycle.	Drug: SB497115 SB497115/Placebo will be administered for at least 2 cycles. Additional cycles are permited if: 1) chemotherapy is continued, 2) the subject appears to be benefitting from the study drug, and 3) the subject has not encountered greater than moderate toxicity with the study drug. The maximum number of cycles would be 8.
Placebo Comparator: Placebo Arm Placebo administered orally daily on days 2 through 11 of each 21-day cycle.	Other: Placebo Placebo administered orally daily on days 2 through 11 of each 21-day cycle.

Outcome Measures

Primary Outcome Measures

Change in baseline platelet count from the first day of the second cycle of chemotherapy to the lowest count observed (nadir) during the cycle(21 days) [throughout entire study]

Secondary Outcome Measures

Safety and tolerability, pharmacodynamics, changes in platelet count during cycle 1(21 days) and beyond cycle 2(21 days), population PK, and deliver intended doses of chemotherapy without thrombocytopenia related AEs [Throughout entire study]
Safety and tolerability as indicated by physical exam, 12-lead ECGs, ophthalmologic examinations, clinical laboratory tests, clinical monitoring/observation, and AE reporting [throughout study]
Pharmacodynamic parameters including platelet count, grade of thrombocytopenia,serum thrombopoietin, and platelet aggregation/activation during the first and second cycles of carboplatin/paclitaxel [During first and second cycles of carboplatin/paclitaxel]
Change in platelet count from day 1 (baseline) to nadir during the first cycle and beyond the second cycle of carboplatin/paclitaxel [throughout study]
Population PK of SB-497115, including clearance (CL/F), absorption rate constant(ka), and volume of distribution (V/F) with assessment of demographic covariates influencing SB-497115 PK [throughout study]
The relationship between PK of SB-497115 andrelevant safety and efficacy endpoints will be explored [throughout study]
Dose intensity (percent of intended dose) of carboplatin/paclitaxel []
Carboplatin/paclitaxel-associated thrombocytopenia-related AEs, as defined by NCI []
Common Terminology Criteria for Adverse Events, CTCAE v3.0, to include the number of platelet transfusions, bleeding events (hematoma), hemorrhage/bleeding,petechiae/purpura), clinical laboratory tests, and clinical observations [throughout study]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Subjects ≥18 years old, who are chemotherapy naïve, with histologically or cytologically confirmed advanced solid tumor (leukemia and lymphoma are excluded) who are scheduled to received carboplatin/paclitaxel as shown below. For the purpose of this study, advanced tumors are defined as tumors that are being treated with palliative intent (i.e., not being treated with curative intent).
Subjects scheduled to receive first-line chemotherapy as carboplatin AUC 5-6 IV over 30 minutes plus paclitaxel 175-225 mg/m2 IV over 3 hours on day 1 every 21 days, with routine pre-medications, i.e., 20 mg dexamethasone [or equivalent] orally 6 and 12 hours pre-paclitaxel, 50 mg IV diphenhydramine [or equivalent] and 300 mg IV cimetidine [or equivalent] 30-60 minutes pre-paclitaxel.
ECOG-Zubrod performance status is 0, or 1.
Subject has no history of platelet disorders or dysfunction and no history of a bleeding disorder.
Subjects have adequate:

hematologic function (ANC ≥ 1,500/mm3, hemoglobin ≥ 9 g/dL, and platelet count ≥100,000/mm3 and < upper limit of normal range (eg, 400,000 to 450,000/mm3), hepatic function (bilirubin ≤ 2 mg/dL and alanine aminotransferase ≤ three times the upper limit of normal), renal function (creatinine ≤ 2.0 mg/dL).

Subject has no physical limitation to ingest and retain oral medication.
Subject has life expectancy of at least 6 months.
Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of nonchildbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal > 1 year), or of childbearing potential and use one of the following acceptable methods of contraception from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:

Complete abstinence from intercourse; Intrauterine device (IUD); Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide); Male partner is sterile prior to entry into the study and is the only partner of the female; Systemic contraceptives (combined or progesterone only).

Subject is able to understand and comply with protocol requirements and instructions and intend to complete the study as planned.
Subject has signed and dated written informed consent.
Chemotherapy naive patients with advanced solid tumors (without brain metastasis or rapid progression within 2 weeks) who are scheduled to receive standard first-line therapy with carboplatin and paclitaxel every 21 days.
Adequate hematologic, hepatic and renal function.

Exclusion criteria:

Any clinically relevant abnormality, other than cancer, identified on the screening examination, or any other medical condition or circumstance, which in the opinion of the Investigator, makes the subject unsuitable for participation in the study and/or would make the patient's data difficult to interpret.
Subjects with a known history of rapidly progressive disease (marked increase in tumor size [>50%], ascites, or serious symptoms related to underlying cancer in the preceding 4-week period), surgery within the previous 2 weeks, radiotherapy within the previous 4 weeks, or any prior chemotherapy.
Subjects with known pre-existing cardiac disease, including congestive heart failure, arrhythmias requiring treatment, or myocardial infarction within the preceding 3 months.
Subjects with abnormal resting 12-lead ECG at screening that would indicate preexisting cardiac disease, as noted in exclusion criterion 3.
Subjects with known clotting disorder associated with hypercoaguability.
Subject has consumed aspirin, aspirin-containing compounds, salicylates, quinine or non-steroidal anti-inflammatories (NSAIDs) for > 3 consecutive days within 2 weeks of the study start and would require them at any time during the study.
Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
Subject has consumed liquid antacids (e.g. Maalox, Mylanta, Amphogel, milk of magnesia), chewable antacids (e.g. TUMS) or calcium supplements within 48 hours of the first dose of study medication, and/or will require these medications during the study.
Subject has consumed rosuvastatin or pravastatin within 1 week of the first dose of study medication and/or will require these medications at any time during the study.
Any history of drug-induced thrombocytopenia (e.g., quinine).
Systemic anti-coagulant use within 4 weeks prior to study entry.
Consumption of any herbal or dietary supplements, excluding vitamin or mineral supplements (See Exclusion 8 for calcium supplements), within 1 week of the study start.
Female subjects who are lactating or have a positive beta-hCG at screening.
Subjects with a history of CNS metastases or clinical signs or symptoms of brain and/or leptomeningeal metastases confirmed by CT or MRI brain scan.
History of platelet or bleeding disorders.
Patients using aspirin, aspirin-containing compounds, salicylates, antacids, rosuvastatin, pravastatin, non-steroidal anti-inflammatory drugs for greater than 3 days during and within 3 weeks prior to the study.
Females who are pregnant or breastfeeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Tucson	Arizona	United States	85715
2	GSK Investigational Site	Jonesboro	Arkansas	United States	72401
3	GSK Investigational Site	Greenbrae	California	United States	94904-2007
4	GSK Investigational Site	Long Beach	California	United States	90813
5	GSK Investigational Site	Los Angeles	California	United States	90033
6	GSK Investigational Site	Los Angeles	California	United States	90095
7	GSK Investigational Site	Colorado Springs	Colorado	United States	80907
8	GSK Investigational Site	Newark	Delaware	United States	19718
9	GSK Investigational Site	Boca Raton	Florida	United States	33428
10	GSK Investigational Site	Hollywood	Florida	United States	33021
11	GSK Investigational Site	Tamarac	Florida	United States	33321
12	GSK Investigational Site	Savannah	Georgia	United States	31405
13	GSK Investigational Site	Metairie	Louisiana	United States	70006
14	GSK Investigational Site	Baltimore	Maryland	United States	21237-3998
15	GSK Investigational Site	Minneapolis	Minnesota	United States	55455
16	GSK Investigational Site	Hattiesburg	Mississippi	United States	39401
17	GSK Investigational Site	Tupelo	Mississippi	United States	38801
18	GSK Investigational Site	Las Vegas	Nevada	United States	89102
19	GSK Investigational Site	Babylon	New York	United States	11702
20	GSK Investigational Site	New York	New York	United States	10032
21	GSK Investigational Site	Durham	North Carolina	United States	27707
22	GSK Investigational Site	Akron	Ohio	United States	44304
23	GSK Investigational Site	Mayfield Heights	Ohio	United States	44124
24	GSK Investigational Site	Toledo	Ohio	United States	43614-5809
25	GSK Investigational Site	Bryan	Texas	United States	77802
26	GSK Investigational Site	Ogden	Utah	United States	84403
27	GSK Investigational Site	Salem	Virginia	United States	24153
28	GSK Investigational Site	Capital Federal	Buenos Aires	Argentina	C1405BCK
29	GSK Investigational Site	La Plata	Buenos Aires	Argentina	1900
30	GSK Investigational Site	Rosario	Santa Fe	Argentina	2000
31	GSK Investigational Site	Rosario	Santa Fe	Argentina	S2000KZE
32	GSK Investigational Site	Buenos Aires		Argentina	1425
33	GSK Investigational Site	Buenos Aires		Argentina	C1416DRW
34	GSK Investigational Site	Vienna		Austria	A-1090
35	GSK Investigational Site	Vienna		Austria	A-1100
36	GSK Investigational Site	Vienna		Austria	A-1140
37	GSK Investigational Site	Plovdiv		Bulgaria	4000
38	GSK Investigational Site	Sofia		Bulgaria	1527
39	GSK Investigational Site	Sofia		Bulgaria	1756
40	GSK Investigational Site	Sofia		Bulgaria	1784
41	GSK Investigational Site	Brno		Czech Republic	656 53
42	GSK Investigational Site	Praha 8		Czech Republic	180 81
43	GSK Investigational Site	Freiburg	Baden-Wuerttemberg	Germany	79106
44	GSK Investigational Site	Regensburg	Bayern	Germany	93049
45	GSK Investigational Site	Marburg	Hessen	Germany	35033
46	GSK Investigational Site	Hemer	Nordrhein-Westfalen	Germany	58675
47	GSK Investigational Site	Trier	Rheinland-Pfalz	Germany	54290
48	GSK Investigational Site	Grosshansdorf	Schleswig-Holstein	Germany	22927
49	GSK Investigational Site	Bad Berka	Thueringen	Germany	99437
50	GSK Investigational Site	Berlin		Germany	13353
51	GSK Investigational Site	Hamburg		Germany	21075
52	GSK Investigational Site	Budapest		Hungary	1529
53	GSK Investigational Site	Székesfehérvár		Hungary	8000
54	GSK Investigational Site	Bangalore		India	560 034
55	GSK Investigational Site	Hyderabad, Andhra Pradesh		India	500482
56	GSK Investigational Site	Kolkatta		India	700 054
57	GSK Investigational Site	Vellore		India	632 004
58	GSK Investigational Site	Benevento	Campania	Italy	82100
59	GSK Investigational Site	Roma	Lazio	Italy	00168
60	GSK Investigational Site	Milano	Lombardia	Italy	20141
61	GSK Investigational Site	Campobasso	Molise	Italy	86100
62	GSK Investigational Site	Seoul		Korea, Republic of	135-710
63	GSK Investigational Site	Seoul		Korea, Republic of	138-736
64	GSK Investigational Site	Merida	Yucatán	Mexico	97500
65	GSK Investigational Site	Lima		Peru	Lima 34
66	GSK Investigational Site	Olsztyn		Poland	10-228
67	GSK Investigational Site	Poznan		Poland	60-569
68	GSK Investigational Site	Poznan		Poland	61-866
69	GSK Investigational Site	Szczecin		Poland	70-891
70	GSK Investigational Site	Wroclaw		Poland	53-413
71	GSK Investigational Site	Bucuresti		Romania	022328
72	GSK Investigational Site	Moscow Region		Russian Federation	143 423
73	GSK Investigational Site	Moscow		Russian Federation	115 478
74	GSK Investigational Site	Moscow		Russian Federation	117997
75	GSK Investigational Site	Moscow		Russian Federation	129301
76	GSK Investigational Site	St. Petersburg		Russian Federation	197758
77	GSK Investigational Site	St. Petersburg		Russian Federation	198255
78	GSK Investigational Site	Badalona		Spain	08916
79	GSK Investigational Site	Barcelona		Spain	08036
80	GSK Investigational Site	Cordoba		Spain	14004
81	GSK Investigational Site	Madrid		Spain	28006
82	GSK Investigational Site	Santa Cruz de Tenerife		Spain	38320
83	GSK Investigational Site	Santander		Spain	38008
84	GSK Investigational Site	Sevilla		Spain	41014
85	GSK Investigational Site	Taipei		Taiwan	100
86	GSK Investigational Site	Tau-Yuan County		Taiwan	333
87	GSK Investigational Site	Dnepropetrovsk		Ukraine	49102
88	GSK Investigational Site	Donetsk		Ukraine	83092
89	GSK Investigational Site	Kyiv		Ukraine	03115
90	GSK Investigational Site	Lvov		Ukraine	79031
91	GSK Investigational Site	Truro	Cornwall	United Kingdom	TR1 3LJ
92	GSK Investigational Site	Chelmsford	Essex	United Kingdom	CM1 7ET
93	GSK Investigational Site	Colchester		United Kingdom	CO3 3NB
94	GSK Investigational Site	Dundee		United Kingdom	DD1 9SY
95	GSK Investigational Site	Leicester		United Kingdom	LE1 5WW